Serine catabolism generates liver NADPH and supports hepatic lipogenesis

Liver and adipose tissue are shown to use different metabolic routes to generate NADPH for de novo lipogenesis, with the liver relying on a unique cytosolic serine catabolic pathway involving the enzyme SHMT1. Carbohydrate can be converted into fat by de novo lipogenesis, a process upregulated in fatty liver disease. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor. The feedstocks used to generate acetyl-CoA and NADPH in lipogenic tissues remain, however, unclear. Here we show using stable isotope tracing in mice that de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH. The liver, in contrast, derives acetyl-CoA for lipogenesis from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway in liver running in the opposite direction to that observed in most tissues and tumours, with NADPH made by the SHMT1-MTHFD1-ALDH1L1 reaction sequence. SHMT inhibition decreases hepatic lipogenesis. Thus, liver folate metabolism is distinctively wired to support cytosolic NADPH production and lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are used, opening the door to tissue-specific pharmacological interventions.

Automated summary

The liver relies on a unique cytosolic serine catabolic pathway for NADPH generation, while adipose tissue uses the pentose phosphate pathway. Acetyl-CoA for lipogenesis in liver is derived from acetate and lactate, whereas in adipose tissue glucose is the main substrate. Despite using the same enzymes, different substrates are utilized, highlighting the potential for tissue-specific pharmacological interventions.